N,n&#39;-bis-(3-phenoxy-2-hydroxy-propyl)-alkenediamines and salts thereof

ABSTRACT

Compounds of the formula   WHEREIN R1 is -OH; -COOH; -CONH2; -NO2; -CF3; halogen; alkyl of 4 to 5 carbon atoms; alkoxy of 4 to 5 carbon atoms; alkenyl of 3 to 5 carbon atoms; alkynyl of 2 to 5 carbon atoms; alkenyloxy of 3 to 5 carbon atoms; alkynyloxy of 3 to 5 carbon atoms; acyl; alkylthio of 1 to 4 carbon atoms; hydroxyalkyl of 1 to 5 carbon atoms; aryl; aryl-lower alkyl; aryloxy; arylamino; aryl-lower alkoxy; aryloxy-lower alkyl; cycloalkyl of 3 to 7 carbon atoms; alkoxyalkyl of 2 to 4 carbon atoms; alkylsulfonylamido of 1 to 4 carbon atoms; dialkylsulfonamido of 2 to 8 carbon atoms; -(CH2)x-CN; -(CH2)x-NH2; -(CH2)x-NH-COOR5; -(CH2)x-NH-acyl; -(CH2)x-NH-CO-NR6R7; -COOR; where X IS 0, 1, 2 OR 3, R is alkyl of 1 to 4 carbon atoms, R5 is alkyl of 1 to 3 carbon atoms, and R6 and R7 are each hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl of 3 to 5 carbon atoms or, together with each other and the nitrogen atom to which they are attached, a 5- to 6membered heterocycle; OR, WHERE R4 is other than hydrogen, also alkyl of 1 to 3 carbon atoms or alkoxy of 1 to 3 carbon atoms; R2 is hydrogen, halogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, alkenyl of 2 to 5 carbon atoms or alkenyloxy of 2 to 5 carbon atoms; R3 is hydrogen, halogen, alkyl of 1 to 5 carbon atoms or alkoxy of 1 to 5 carbon atoms; R2 and R3, together with each other, form a saturated or unsaturated carbocyclic ring or heterocyclic ring; R4 is hydrogen, alkyl of 1 to 5 carbon atoms or aralkyl; and N IS AN INTEGER FROM 1 TO 10, INCLUSIVE; AND THEIR NON-TOXIC, PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS; THE COMPOUNDS AS WELL AS THEIR SALTS ARE USEFUL AS Beta ADRENERGIC BLOCKING AGENTS AND HYPOTENSIVES.

United States Patent [191 Koppe et a1.

[ 1 June 10, 1975 l l N,N'-BlS-(3-PHENOXY-2-HYDROXY- PROPYL)-ALKENED1AMINES AND SALTS THEREOF [73] Assignee: Boehringer lngelheim GmbH,

lngelheim am Rhein, Germany [22] Filed: Feb. 27, 1973 [21] Appl. No: 336,269

[30] Foreign Application Priority Data Mar. 6, 1972 Germany.... 2210620 Dec, 11, 1972 Germany 2260444 [52] U.S. C1. ..260/465 E; 260/247.2 A; 260/256.4 C; 260/268 C; 260/293.75;

260/519; 260/553 R; 260/556 AR;

Primary Examiner-Lewis Gotts Assistant Examiner-Dolph H. Torrence Attorney, Agent, or FirmHammond & Littell [57] ABSTRACT Compounds of the formula atoms; alkynyl of 2 to 5 carbon atoms; alkenyloxy of 3 to 5 carbon atoms; alkynyloxy of 3 to 5 carbon atoms; acyl; alkylthio of 1 to 4 carbon atoms; hydroxyalkyl of l to 5 carbon atoms; aryl: aryl-lower alkyl; aryloxy; arylamino; aryl-lower alkoxy; aryloxy-lower alkyl; cycloalkyl of 3 to 7 carbon atoms; alkoxyalkyl of 2 to 4 carbon atoms: alkylsulfonylamido of 1 to 4 carbon atoms: dialkylsulfonamido of 2 to 8 carbon atoms; 2)1

COOR;

where xis0,1,20r3,

R is alkyl of l to 4 carbon atoms,

R is alkyl of 1 to 3 carbon atoms, and

R and R are each hydrogen, alkyl of l to 4 carbor atoms, alkenyl of 3 to 5 carbon atoms or, together with each other and the nitrogen atom to whicl they are attached, a 5- to 6-memberec heterocycle;

or, where R, is other than hydrogen, also alkyl of l to 3 carbon atoms or alkoxy of l to 3 carbor atoms;

R is hydrogen, halogen, alkyl of l to 5 carbor atoms, alkoxy of l to 5 carbon atoms, alkenyl o'. 2 to 5 carbon atoms or alkenyloxy 'of 2 to 5 carbon atoms;

R, is hydrogen, halogen, alkyl of 1 to 5 carbor atoms or alkoxy of 1 to 5 carbonatorns;

R and R together with each other, form 2 saturated or unsaturated carbocyclic ring 0: heterocyclic ring;

R, is hydrogen, alkyl of 1 to 5 carbon atoms or aralkyl; and

n is an integer from 1 to 10, inclusive;

and their non-toxic, pharmacologically acceptable acid addition salts; the compounds as well as their 0011 -CHOH-CH2-N- CH2 -l?-CH2CHQH-CH2-O 2 R1, Rn

wherein R, is -O1-1; -COOH; CONH -NO CF halogen; alkyl of 4 to 5 carbon atoms; alkoxy of 4 to 5 carbon atoms; alkenyl of 3 to 5 carbon salts are useful as B-adrenergic blocking agents and hypotensives.

4 Claims, No Drawings Rh, Ra

wherein R is OH; COOH; CONH- NO CF halogen; alkyl of 4 to 5 carbon atoms; alkoxy of 4 to 5 carbon atoms; alkenyl of 3 to 5 carbon atoms; alkynyl of 2 to 5 carbon atoms; alkenyloxy of 3 to 5 carbon atoms; alkynyloxy of 3 to 5 carbon atoms; acyl; alkylthio of 1 to 4 carbon atoms; hydroxyalkyl of 1 to 5 carbon atoms; aryl; aryl-lower alkyl; aryloxy; arylamino; aryl-lower alkoxy; aryloxy-lower alkyl; cycloalkyl of 3 to 7 carbon atoms; alkoxyalkyl of 2 to 4 carbon atoms; alkylsulfonylamido of l to 4 carbon atoms; dialkylsulfonamido of 2 to 8 carbon atoms;

where xisO,1,2or3,

R is alkyl of 1 to 4 carbon atoms;

R is alkyl of l to 3 carbon atoms, and

R and R are each hydrogen, alkyl of l to 4 carbon atoms, alkenyl of 3 to 5 carbon atoms or, together with each other and the nitrogen atom to which they are attached, a 5- to 6-membered heterocycle;

or, when R is other than hydrogen, also alkyl of 1 to 3 carbon atoms or alkoxy of l to 3 carbon atoms;

R is hydrogen, halogen, alkyl of l to 5 carbon atoms,

alkoxy of l to 5 carbon atoms, alkenyl of 2to 5 carbon atoms or alkenyloxy of 2 to 5 carbon atoms;

R is hydrogen, halogen, alkyl of l to 5 carbon atoms or alkoxy of l to 5 carbon atoms;

R and R together with each other, form a saturated or unsaturated carbocyclic ring or heterocyclic ring;

R., is hydrogen, alkyl of l to 5 carbon atoms or aralkyl; and

n is an integer from 1 to 10, inclusive; and their non-toxic, pharamcologically acceptable acid addition salts.

In the definition of substituent R in formula I above, the preferred embodiments of alkyl of 4 to 5 carbon atoms are tert.butyl or tert.amyl; the preferred embodiment of alkenyl is ally]; the preferred embodiment of alkynyl is ehtynyl; the preferred embodiments of alkenyloxy and alkynyloxy are allyloxy and proparglyloxy, respectively; the preferred embodiments of acyl are aliphatic acyl of 1 to 5 carbon atoms and aromatic acyl of 7 to l 1 carbon atoms, the latter optionally having a halogen, lower alkyl or lower alkoxy substituent attached thereto; the preferred embodiments of hydroxyalkyl are hydroxymethyl and hydroxyethyl; the preferred embodiments of aryl are aryl of 6 to 10 carbon atoms, optionally having a halogen, lower alkyl or lower alkoxy substituent attached thereto; the preferred embodiments of alkyland dialkylsulfonylamido are methyland dimethylsulfonylamido, respectively; the preferred embodiment of R is methyl; the preferred embodiments of the acyl moiety in (CH ),NHacyl are alkanoyl of l to 4 carbon atoms and benzoyl; and the preferred embodiments of the heterocycle formed by R and R are piperidino, piperazineo, morpholino and pyrimidino.

The preferred embodiments of the carbocyclic and heterocyclic rings formed by R and R are naphthyl, tetrahydronaphthyl, indanyl and indolyl.

The compounds embraced by formula 1 above may be prepared by the following methods:

Method A By reacting a compound of the formula -0-cH -z (II) wherein R, to R have the meanings defined above, and Z is CHjHg or CH-CH HE].

(Hal halogen), with an alkylenediamine of the formula wherein R and n have the meanings defined above.

Method B By reacting a compound of the formula wherein R to R -have the meanings previously defined, with an alkylenedihalide of the formula wherein n and Hal have the above-defined meanings. The reaction proceeds in 2 steps with intermediate formation of a compound of the formula 3,888, 3 1 -OCH -CHOHCH -1:I-(CH -Hal 3 (VI I wherein R to R n and Hal have the meanings defined above. It is also possible to produce a compound of the formula I directly from a compound of the formula VI by reacting it with a compound of the formula IV.

Method C By splitting off an easily removable protective group wherein R to R and n have the above-defined meanings and G is hydrolytically removable group such as acyl or acetal.

Method D By splitting off a protective group from a bis-tertiary amine of the formula 1 -O-CH H-CH -1:I-(CH R on Sch -N-CH2-CH-CH2-O- (VIII) 1 l Sch OH 2 4 wherein R to R and n have the above-defined meanings and Sch is an easily removable amino-protective group, such as benzyl. This method leads to compounds of the formula I wherein R is hydrogen.

Method E By alkylating a compound of the formula -o-cH -cH-cn -NH-(cH R on -NH-cH -oH-cH -o- (IX) R OH R3 2 wherein R to R and n have the above defined meanings, for example with an electrophilic compound of the formula R -X, wherein R, has the meaning previously defined and X is an anionically easily removable 4 group, such as halogen or alkyl or aryl-sulfonyl, or with an aliphatic ketone corresponding to radical R under reducing conditions.

Further methods for producing the compounds of the formula I include, for example, converting a starting compound wherein the bis-(aryloxypropanolamine)- alkylene structure is already present, but one of the substituents, such as CN, is still missing or only present in the form of a precursor into a compound of the formula I by introducing the missing substituent or by converting the precursor of the substituent into the substituent-CN. I

For example, the following methods are illustrative thereof.

Method F A compound of the formula -O-CH-CH-CHg-N-'(CI-Ig) I I R2 OH an -N-CH -CH-CHg-O (x) l I Ru, OH k R? wherein R and R and n have the previously defined meanings and A represents a group convertible into R pursuant to conventional methods, such as CONH or CH=NOI-l group (convert into -CN by dehydration), or an amino group (converts into cyano by diazotization and heating with copper(I)-cyanide), may be converted into a compound of the formula I by applying the respective conventional treatment required in each case, i.e., dehydration or diazotization and heating with a copper-l-salt.

The compounds of the formula X already comprise the finished bis-(aryloxypropanolamine)-alkylene structure and may therefore be prepared pursuant to method A. In case A represents an NH -group, it is advantageously obtained by reduction of the corresponding nitro compound. In case A represents a COOH- group, it is obtained by saponification of a cyano or an ester group. A hydroxyalkyl group may be obtained by hydrolysis of the corresponding haloalkyl group or by splitting of an acyloxyalkyl group by hydrolysis or hydrogenation.

Method G A compound of the formula Ar-0-CH -CH-CH -N-(CH2) -N-CH -CH-CH -O-Ar (XI) Ru OH wherein R and n have the previously defined meanings and Ar is it is further possible to prepare a compound of the formula I by:

Method H Reacting a compound of the formula wherein R to R and n have the previously defined meanings, with a compound of the formula II.

A compound of the formula I may also be prepared by:

wherein R.,, n and Z have the previously defined meanings, with a phenol of the formula (XIIa) wherein R to R have the previously defined meanings,

or with a salt thereof. This method is primarily suitable for the preparation of a compound of the formula I wherein R is alkyl.

Most of the starting compounds of the formulas II to XIII are known. Those which are not'known may be prepared by conventional methods. Thus, an epoxide of the formula II may be obtained by reacting the corresponding phenol of the formula XIII or a salt thereof (preferably an alkali metal salt) with epichlorohydrin; a halohydrin of the formula II may be otained by cleavage of the epoxide with the corresponding hydrohalic acid.

A compound of the formula III wherein R is alkyl may be obtained-from the corresponding compound of the formula III wherein R is hydrogen, by treatment with a conventional alkylating agent R -X (X radical of a reactive ester, such as halogen or toluenesulfonyloxy). Secondary alkyl groups may also be obtained by reductive amination with the corresponding ketone, such as acetone, and NaBI-I A compound of the formula IV may be obtained by reacting a compound of the formula iI with an amine of the formula NH R where R 'has the meanings defined above.

A compound of the-formula V is obtainable from a corresponding dialcohol I-IO(CI-I ),,OI-I by reaction with a conventional halogenating agent, such as SOCl or PCl A compound of the formula VI may be prepared by reacting a corresponding haloalkylamine of the formula wherein R.,, n and Hal have the previously defined meanings, with a compound of the formula II.

A compound of the formula VII may be prepared from a halohydrin of the formula II by reacting the latter with a conventional acylating or acetalizing agent, such as acetyl chloride or tetrahydropyranyl ether, and subsequently reacting the intermediate compound of the formula -OCHg-CH-CH -Ha1 (Xv) wherein R, to R G and Hal have the previously defined meanings, with a compound of the formula III.

A compound of the formula VIII is advantageously prepared by reacting a compound of the formula II with a diamine of the formula SchHN-(CH ),,NHSch XVI.

wherein Sch and n have the previously defined meanings. A compound of the formula XVI may be produced from a compound of the formula III wherein R is hydrogen by reacting the latter with a conventional reagent for forming protective groups, such as benzyl bromide, acetyl chloride or carbobenzoxy chloride.

The compounds of the formulas IX to XI already contain the bis-(aryloxypropanolamine)-alkylene structure; therefore, they may be obtained with the aid of method B, where substitution of the phenyl moities of the compound of the formula II has to correspond to that of the desired intermediate product of the formulas IX, X or XI.

A compound of the formula XII may be obtained by reacting a compound of the formula VI (the preparation of which has been described above) with an amine of the formula NI-I R where R, has the meanings defined above.

A compound of the formula XIIa may be obtained from a compound of the formula III by reacting the latter with epichlorohydrin. A halohydrin of the formula XIIa thus obtained may be converted into an epxoide of the formula XIIa by means of aqueous sodium hydroxide.

The compounds embraced by formula I possess two asymmetric carbon atoms and occur therefore as racemates, as well as in the form of optical antipodes. The racemates may be separated with the aid of optically active auxiliary acids, such as di-0,0-p-toluyl-D- tartaric acid, into their optical antipode components.

the compounds of the formula I, both in the form of racemates or optical antipodes, form acid addition salts with inorganic or organic acids. Examples of non-toxic, pharmacologically acceptable acid addition salts are those formed with hydrochloric acid, hydrobromic acid, sulfuric acid, maleic acid, lactic acid, methanesulfonic acid, oxalic acid, tartaric acid, 8- chlorotheophylline or the like.

The following examples further illustrate the present invention and will enable others skilled in the art to understand it more completely. It should be understood, however, that the invention is not limited solely to the particular examples given below.

EXAMPLE 1 N,N'-Bis-[2-hydroxy-3-(2'-allyl'phenoxy)-l-propyllethylene-diamine 2 HQ by method A 19 gm (0.] mol) of l-(2'-allyl-phenoxy)-2,3- epoxypropane was dissolved in 150 ml of ethanol. 3 gm (0.05 mol) of ethylenediamine were added, and the mixture was refluxed for 2 hours. After havingcooled off, the solvent was distilled off, and the residue was dissolved in dilute HCl. Insoluble matter was separated, and the aqueous solution was made alkaline with NaOl-l. The precipitated basic components were extracted with ether, and the organic phase was separated, washed with water and dried over MgSO After having distilled off the ether, 13 gm of residue remained, which were dissolved in little ethanol and admixed with ehtereal l-lCl. The precipitate was recrystallized twice from methanol, subsequently digested with water, vacuum-filtered off and dried, yielding 4.5 gm of the compound of the formula CHg=CH- H2 which had a melting point of 248-251C.

EXAMPLE 2 N,N'-bis-[2'-hydroxy-3'-(3"-hydroxymethylphenoxy)-l '-propyl]-l ,4-butylenediamine 2 HCl by method A 12 gm (0.066 mol) of l-(3'-hydroxymethylphenoxy)-2,3-epoxy-propane were refluxed in 100 ml of ethanol with 2.93 gm (0.033 mol) of 1,4- diaminobutane for 2 hours. After having distilled off the solvent, the residue was dissolved in ethanol and ethereal HCl was added. The hydrochloride precipitated as a viscous oil. It was digested several times with ether and then boiled with ethanol. After cooling, a colorless crystalline substance (3.4 gm) was obtained, which, upon recrystallization from methanol by addition of ether, melted at 189l90C. It was identified to be the compound of the formula CHQOH CHg-CHOH-CHp-O .2Hct

EXAMPLE 3 N,N-bis-[2'-hydroxy-3 2 '-cyano-phenoxy)- l propyl]-],4-diamino-butane 2 HCl by method A 20 gm (0.1 14 mol) of l-(2'-cyano-phenoxy)-2,3- epoxy-propane and 3.7 gm (0.042 mol) of l,4-diamino' butane were refluxed in 100 ml of methanol for 2' hours. After having distilled off the methanol, the residue was dissolved in ethanol and acidified with ethereal HCl. The precipitated crystalline substance was recrystallized from methanol, yielding 3.5 gm of the compound of the formula which had a melting point of 227228C EXAMPLE 4 N,N -bis-[ 2-hydroxy-3 2' '-a llyloxy-phenoxy l propyll-l,2-ethylenediamine 2 HCI by method A -CHQ-CH=CHP -O-CH -CHOH-CH -NH- CH -NH O-CHp-CH=CH2 which had a melting point of l8 8-l90C.

EXAMPLE 5 N,N -bis- 2 -hydroxy-3 '(4' acetylamino-phenoxy l propyl]-l,6-hexamethylenediamine by method A 20.7 gm (0.1 mol) of l-(4'-acetylamino-phenoxy)- 2,3-epoxy-propane were refluxed with 5.8v gm (0.05

mol) of 1,6-hexamethylenediamine in 200 ml of ethano] for 2 hours. After cooling, the reaction product was isolated as a colorless crystalline substance and recrystallized several times from methanol, yielding 5.8 gm of the compound of the formula (CH k-NH-CH -CHOH-tffi 1 V v O-QNH (i=0 0H3 which had amelting point of l79-l8lC.

EXAMPLE 6 N,N'-bis-[2'-hydroxy-3 '-(2"-cyano-phenoxy )-l propyl]-l ,6-hexamethylenediamine 2 HCl by method A 87.5 gm (0.5 mol) of"l-(2'-cyano-phenoxy)-2,3-

epoxy-propane were refluxed with 29 gm (0.25 mol) of hexamethylenediamine in 750 ml of methanol for 3 hours. After having distilled off the solvent, the residue was treated with about 700 ml of dilute HCl, and insoluble matter was separated. The aqueous phase fractionally made alkaline with NaOH, and the basic fractions precipitating between pH 7.5 and 8.5 were taken up in ether and washed with water. After drying and distilling off the ether, 16 gm of the free base remained behind, which were dissolved in methanol and acidified with alcoholic l-lCl. Upon addition of ether, 9 gm of the analytically pure hydrochloride, m.p. 200203C, crystallized out.

EXAMPLE 7 N,N-bis-[2'-hydroxy-3-(2"- hydroxycarbonylphenoxy)-l-propyl]-1,2- ethylenediamine 2 HC] by method F 8.5 gm of N,N'-bis-[2-hydroxy-3'-(2"-cyanophenoxy)-l-porpyl]-1,2-ethylenediamine were refluxed for 5 hours in a mixture of 20 ml. of NaOH and 80 ml of water, whereby the diamine dissolved. After cooling, the free acid precipitated out in form of crystals upon acidification with dilute l-lCl. It was separated by vacuum filtration and recrystallized from water, yielding 3.5 gm of the compound of the formula COOH -O-CH -CHOH-CH -NH-(C g) COOH NH-CH2-CHOH-CH2-O -2HC1 which had a melting point of 263 266C.

EXAMPLE 8 tolyloxy)-l -propyl]-1,2-ethylenediamine dioxalate by method B 22.3 gm (0.1 mol) of l(m-tolyloxy)-3-isopropylamino- 2-propanol were refluxed with 9.5 gm (0.05 mol) of ethylene-1,2-dibromide and 12.6 gm (0.15 mol) of sodium bicarbonate in a mixture of 100 ml of tetrahydrofuran and 25 ml of dimethylformamide for 17 hours, while stirring. After having distilled off the solvent, the residue was acidified with dilute HCl, extracted twice with CHCl the organic phase was After distilling off the ether, the residue was dissolved in acetone, and the solution was admixed with a solution of oxalic acid in acetone. After addition of ether, the oxalate separated out as a viscous substance. It was recrystallized from acetonitrile, yielding 4 gm of the compound of the formula which had a melting point of 80C.

EXAMPLE 9 N,N-bis-[2-hydroxy-3 -(4"-amino-phenoxy)-l propyl]-l,4-butylenediamine by method F 3.5 gm (0.0073 mol) of N,N'-bis-[2'-hydroxy-3- (4-nitro-phenoxy)-l-propyl]-1,4-butylenediamine were hydrogenated in 50 ml of methanol in the presence of Raney nickel at room temperature and atmospheric pressure. After the absorption of hydrogen had terminated, the catalyst was separated, the solvent was distilled off, and the viscous residue was boiled with ethyl acetate. The base separated out after cooling as colorless crystallizate, which was separated and recrystallized once more, yielding 2.2 gm of the above named product which had a melting point of lO5l08C.

Analogous to Example 3 (method A) the following additional compounds of the formula I were prepared from the corresponding epoxide of the formula ll and the corresponding alkylenediamine of the formula III:

\R2 washed with water and dried over HgS0 and the CHC1 was distilled off. The residue (19 gm) was: it digested with water, vacuum-filtered and admixed with dilute NaOH. The precipitated basic com- NH H2 2 ponents were taken up in ether, and the organic phase 50 2 was washed with water and dried over MgSO T A B L E Ebtample R R 11 m.p.

No. of hydrochloride 1o a-cw H 2 212-215c 11 '2-CH -CH=CH H i 6 -16sc l2 2-O-CH -CH=CH H 6 133-137C l3 2-CN H 8 l93-l95C 1h Q-CN H 9 l82-185C l5 2-CN H 5 202-20 lC 16 l-NOg H 1 217-2190 13 7 EXAMPLE 48 N,N '-bis-isopropyl-N ,N '-bis[2 -hydroxy-3 2 -cyanophenoxyyl '-propyl]-1,6-hexamethylenediamine 2 HCl by method B 11.7 gm (0.05 mol) of l-(2'-cyano-phenoxy)-3-- isopropylamino-2-propanol were refluxed with 6.1 gm (0.025 mol) of 1,6-dibromohexane in 80 ml of ethanol in the presence of gm (0.06 mol) of NaHCO for 20 hours. Thereafter, the solvent was distilled off, the residue was digested with dilute NaOH, and the basic components were taken up in CHCl The organic phase was washed with water and dried over Na SO After having distilled off the CHCI the viscous residue was purified by column-chromatography. The base was dissolved in a little ethanol, and ethereal HCl was added. The hydrochloride crystallized out in the form of colorless crystals after addition of ether. Yield: 4.5 gm; m. p. 189- 192C.

EXAMPLE 49 N,N'-bis-[ 2'-hydroxy-3 3 ,5 "-dibromo-4' '-aminophenoxy)-1 -propyl]-1,6-hexamethylenediamine 4 l-IBr by method G A mixture consisting of 1.1 gm (0.0025 mol) of N,-

' N '-bis-[ 2 '-hydroxy-3 4' '-amino-phenoxy)- l -propyl 1,-hexamethylenediamine, 12 ml. of 65 l-lBr and 4 ml of water was heated to 45C. While stirring, 1.2 gm (0.01 mol) of 30% H 0 were added. In the course of the resulting exothermic. reaction yellow crystals formed, which were vacuum-filtered off after the reaction had gone to completion. The raw product (2.5 gm) was recrystallized from methanol by addition of ether, yielding 2.1 gm of the compound of the formula HpN '4 H Br which had a melting point of 228-230C.

EXAMPLE '50 N,N'-bis['2'-hydroxy-3 2' -aminomethyl-phenoxy 1-propy1]-l,6-hexamethylenediamine 2 RC1 by method F EXAMPLE 51 Using a procedure analogous to that described in Example 9,, N,N'-bis-[2'-hydroxy-3'-(4"-amino- 14 phenoXy)-1 -propyl]-l ,6-hexamethylenediamine 4 l-lCl, m.p. l29-131C (base), was prepared from N,N- -bis[2-hydroxy-3'-(4"-nitrophenoxy)-1-propyl]-l,6- hexamethylenediamine.

EXAMPLE 52 N,N -bis- 2'-hydroxy-3 2' -hydroxycarbonylphenoxy)-l '-propyl]-1 ,4-tetramethylenediamine 2 HCL by method F 6.7 gm of N,N-bis-[2-hydroxy-3-(2"-cyanophenoxy)-l -propyl]-l ,4-tetramethylenediamine were refluxed in a mixture of 20 ml of aqueous 40% NaOH and ml of water for 8 hours. After cooling, the mixture was acidified. with HCl. The precipitated solid substance was separated and recrystallized from methanol by addition of ether. Yield: 2.4 gm; m.p. 208209C.

EXAMPLE 53 N,N'-bis-[2'-hydroxy-3'-(4"-hydroxycarbonylphenoxy )-1 -propyl]-1 ,4-tetramethylenediamine 2 HCl by method F 5.3 gm of N,N'-bis-[2-hydroxy-3'-(4"- methoxycarbonyl-phenoxy )-1 -propyl]-l ,4- tetramethylenediamine 2 HCl were refluxed with HCl for 3 hours. After cooling, the free base crystallized out and was recrystallized from water. Yield: 4.4 gm; m.p. 293C.

EXAMPLE 54 Using a procedure analogous to that described in Example 53, N,N'-bis-[2'-hydroxy-3'-(4"- hydroxycarbonylphenoxy )-1 '-propyl]-l ,6- hexamethylenediamine 2 BC], m.p. 287288C, was

prepared from N,N -bis-[ 2 -hydroxy-3 '-(4 methoxycarbonyl-phenoxy)-1 -propyl]-l ,6- hexamethylenediamine.

EXAMPLE 55 Using a procedure analogous to that described in Example 53, N,N'-bis-[2'-hydroxy-3'-(4"- hydroxycarbonylphenoxy )-1 '-propyl]-l ,2- ethylenediamine 2 HCl, m.p. 300C, was prepared from N,N'-bis-[2-hydroxy-3'-(4"-methoxycarbonylphenoxy)-1 -propy1]-1 ,2-ethylenediamine.

EXAMPLE 56 N,N -Bis-methyl-N ,N '-bis-[2'-hydroxy-3 2 '-cyanophenoxy)-l '-propyl]-l ,2-ethylenediamine dioxalate by method E A mixture consisting of 4.1 gm (0.01 mol) of N,N- bis-[2'-hydroxy-3 '-(2' '-cyano-phenoxy)-l '-propyl]- 1,2-ethylenediamine, ml of CH OH, 2.8 gm of CH (0.022 mol) and 4 gm of NaHCO was heated at its boiling point for 3 hours. Thereafter, the solvent was distilled off, the residue was digested with dilute NaOH, the base was extracted with Cl-lCl and the organic phase was washed with H 0 and dried over MgSO After distilling off the CHCI the residue was purified by column-chromatography. The fraction containing the pure diamine was evaporated in vacuo, the residue was dissolved in a little methanol, and a solution of oxalic acid in acetone was added. The colorless substance which crystallized out after a short time (1.2 gm) was identified'to be the compound of the formula having a melting point of l52-l54C.

EXAMPLE 57 N,N -Bis-[2 -hydroxy-3 2-cyano-4' ,6"-dichlorophenoxy)-l -propyl]- l ,5-pentamethylenediamine 2 l-lCl by method G 4.52 gm (0.01 mol) of N,N-bis-[2'-hydroxy-3'-(2"- pentamethylenediamine were dissolved in 50 ml of 20 conc. HCl, and the solution was heated to 40'C. While stirring, 2.42 gm of water were added dropwise, whereby the temperature rose to about 60C. After one hour the reaction mixture was cooled, evaporated in vacuo, and the residue, after extraction with ether, was made alkaline with NaOH. The basic components were taken up in Cl-lCl and the organic phase was washed with H and dried over MgSO The CHCI was distilled off, and the residual mixture of bases was columnchromatographically purified. The diamine was dissolved in a little ethanol, and ethereal HCl was added, whereby a colorless substance crystallized out, yielding 0.8 gm of the compound of the formula c1 0-CH2-CHOH-CH2-NH-(CH2)5 Cl CN -NH-CH2-CHOH-CH2-O c1 Using a procedure analogous to that described in Example l, the following compounds were also prepared:

EXAMPLE 58 2 HCl from l-(5 ',6',7',8'-tetrahydro-l -naphthoxy )-2,3- epoxypropane and hexamethylenediamine.

EXAMPLE 59 N,N-Bis-[2'-hydroxy-3 '-(4"-tert.butyl-phenoxy)-l propyl]-1,6-hexamethylenediamine, m.p. 223226C,

"16 from l-(4-tert.butyl-phenoxy)-2,3-epoxy-propane and hexamethylenediamine.

EXAMPLE 6O N,N'-Bis-[2'-hydroxy-3'-(5"-indanyloxy)-l propyl]-1,6hexamethylenediamine dihydrochloride, m.p. 255-258C, of the formula -NH-CH2-CHOH-C Hp-O 2 H01 from 1-(5-indanyloxy)-2,3-epoxy-propane and hexamethylenediamine.

EXAMPLE 61 N,N-Bis-[ 1 -(2"-chloro-5 "-methyl-phenoxy)-2- hydroxy-propyl-3']-butylene-l,4-diamine 2 HCl by method A CH3 c1 which had a melting point of 233235C.

EXAMPLE 62 N,N -Bis- 1 2 -chloro-5 '-methyl-phenoxy)-2 hydroxy-propyl-3'1-l,2-ethylenediamine 2 HC! by method A 10 gm (0.05 mol) of 1-(2chloro-5-methylphenoxy)-2,3-epoxy-propane were dissolved with 1.5 gm (0.025 mol) of ethylenediamine in ml of ethanol. After refluxing the solution for 2 hours, it was cooled with ice water, whereby the reaction product crystallized out which was collected by vacuum filtration and recrystallized from dimethylformamide. The colorless base, which melted at 156 to 160C, was dissolved in methanol and ethereal HCl was added. The precipitate formed thereby was collected, yielding 3.2

gm of the compound named in the heading, which had a melting point of 255260C.

EXAMPLE 63 N,N -Bis-[ 1'-(2 -chloro-5"-methyl phenoxy)-2- hy ro xy-propyl-3 ]-N ,N '-bis-isopropyl-hexamethylene-1,6-diamine 2 HCl by method B 16.8 gm (0.065 mol) of l-(2'-chloro-5'-mcthylphenoxy)3-isopropylamino-propanol-(2) were dissolved in l ml of ethano, 7 gm of NaH(():, were added, and then 7.92 gm (0.0325 mol) of 1,6- dibromohexane were added dropwise. The resulting mixture was refluxed for l0 hours. Subsequently, after distilling off the solvent, the residue was acidified with HCl, the aqueous phase extracted with ether and made alkaline with NaOH. The precipitate was taken up in chloroform, and the solution was washed with water. After drying over MgSO the CHCL, was distilled off, and the residual mixture of bases was separated by column-chromatography. The pure substance (8.4 gm) was dissolved in a little ethanol, alcoholic HCl and ether were added, and the oil which separated out was dissolved in acetonitrile. Upon addition of ether, a colorless crystalline substance separated out which was recrystallized from ethanol by addition of ether, yield ing 6.8 gm of the compound named in the heading, which had a melting point of 187-l89 EXAMPLE 64 N,N '-Bis-[ l -(2-chl0ro-5"-methyl-phenoxy)2- hydroxypropyl-3']-N,N'-bis-methyl-hexamethylene- 1,6-diamine 2 HC] by method D 2.068 gm (0.004 mol) of N,N'-bis-[ l-(2"-chloro- 5"-methyl-phenoxy)-2-hydroxypropyl-3' hexamethylene-l,6-diaminc were mixed with 4.6 gm (0.1 mol) of formic acid and 6 ml of formaline solution, and the mixture was heated to 90C. After the evolution of (0 had started, the temperature was held at 90C for 2 hours. The cooled solution was made alkaline with NaOH, extracted with CHCl and the organic phase was washed with H O and dried over Na. 50;. After distilling off the chloroform, 2.2 gm of a residue were obtained which was dissolved in acetonitrile, and the solution was acidified with alcoholic H(l. The crystalline product formed thereby was recrystallized from methanol by addition ot'ether, yielding 1.8 gm of the compound named in the heading, which had a melting point of l85-l 89C.

EXAMPLE 65 N,N 'Bis-[l -(2"-chloro-5 '-methyl-phenoxy) 2 hydroxypropyl-3' ]-N,N'-bis-benzyl-hexamethylenel,6-diamine 2 HCl by method A which had a melting, point of l85--l88(.

EXAMPLE 66 N,N'-Bis-[ l-92"-chloro-5"-methyl-phenoxy)-2'- hydroxypropyl-fil-hexamethylene-l,6-diamine 2 HCl l4.5 gm (0.019 mol) of N,N'bis-[ l'-(2"-chloro5- methyl-phenoxy )-2'-hydroxy-propyl-3 l-N ,N dibenzyl-hexamethylenel,6-diamine 2 HCI were bydrogenatcd over palladized coal in 200 ml of methanol at 6 atm./"C until absorption of the theoretical quantity of hydrogen. After separation of the catalyst, the solvent was distilled off, and the solid residue was recrystallized twice from ethanol by addition of ether. 5.6 gm of the compound named in the heading, which had a melting point of 2()7-2lt)C, were obtained.

EXAMPLE 67 N,N-bis-l l'-(2"-cyano-phenoxy)-2-hydroxy-propyl- 3 l-propylene-l,3-diamine by method I 9.25 gm (0.0l mol) ofepichlorohydrin were dissolved in 50 ml of ethanol, a solution of 3.7 gm of propylene-l,3-diamine in 30 ml of ethanol was added, and the mixture was heated at 55C for 2 hours, while stirring. Then, the solvent was distilled off, and the residue was purified on a silicagel column. 4.2 gm (0.02 mol) of the isolated N,N'-bis-(2-hydroxy-3-chloropropyl-l )-propylene-l ,3-diamine were dissolved in 20 ml of methanol, and the solution was added dropwise to a solution of 4.8 gm (0.04 mol) of 2-cyano-phenol and 2.2 gm of KOH (0.04 mol) in 30 ml of methanol, while stirring. Then, the mixture was refluxed for 6 hours. After distilling off the solvent, the reaction mixture was separated on a silicagel column. The fractions containing the desired compound were combined, the mixture of solvents was distilled off, the residue was dissolved in a little ethanol, and ethereal HCl was added. The precipitated colorless crystals had a melting point of2 l 7220( and were identified to be the compound of the formula NH-CHg-CHOH-CH -O- The compounds embraced by formula I and their nontoxic, pharmacologieally acceptable acid addition salts have useful pharmacodynamic properties. More particularly, the compounds of the present invention exhibit B-adrenergic receptor blocking and hypotensive activities in warm-blooded animals, such as guinea pigs, cats and dogs.

Of particular significance is the cardio-selective blocking action upon the B-receptors of the heart, i.e.,

the so-called [3,-activity, which the compounds according to the present invention produce.

Therefore, the compounds embraced by formula 1 and their non-toxic, pharmacologically acceptable acid addition salts are useful for the treatment of prophylaxis of disorders of the heart or coronary vessels as well as hypertension in warm-blooded animals.

Particularly effective are those compounds of the formula 1 wherein R is an unsaturated substituent in oor p-position with respect to the side-chain, such as cyano, ethynyl, allyl, allyloxy or propargyloxy. Compounds of the formula I wherein each of the phenyl moieties is mono-substituted with straight or branched hydroxyal kyl are also very effective. Compounds wherein R, is acylamino, such aeetamido, or alkylor dialkylsulfonamido, such as methyl-sulfonamide or dimethylsulfonamido, in or p'position with respect to the side-chain are very good cardioselective B-blockers, as are those compounds of the formula 1 wherein R is p- COOH.

Expecially effective are N,N'-bis-[2'-hydroxy-3'- (2"-cyano-phenoxy)-l 'ln-propyl]-1,6- hexamethylenediamine and its non-toxic, pharmacologically acceptable acid addition salts, for example.

For pharmaceutical purposes the compounds according to the present invention are administered to warmblooded animals pcrorally or parenterally as active in gredients in customary dosage unit compositions, that is, compositions in dosage unit form consisting essentially of an inert pharmaceutical carrier and one effective dosage unit of the active ingredient, such tablets, coated pills, capsules, wafers, powders, solutions, suspensions, emulsions, syrups, suppositories and the like. The effective single dosage unit range of the compounds according to the present invention is from 0.0016 to 5.0 mgm/kg body weight. The preferred oral dosage unit range is 0.016 to 1.0 mgm/lkg body weight, and the preferred parenteral dosage unit range is 0.0016 to 0.5 mgm/kg body weight.

The following examples illustrate a few pharmaceutical dosage unit compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of putting the invention into practical use. The parts are parts by weight unless otherwise specified.

EXAMPLE 68 Tablets The tablet composition is compounded from the following ingredients:

amine 2 HC] 20.0 parts Corn starch 164.0 do. Calcium phosphate 240.0 do. Magnesium stearate 1.0 do.

425.0 parts Preparation:

The individual ingredients are intimately admixed with each other, and the mixture is granulated in the conventional way. Then, the granulate is compressed into 425 mgm-tablets each of which contains mgm of the ethylenediamine compound and is an oral dosage unit composition with effective B-adrenergic receptor blocking and hypotensive action.

methylenediamine 2 HCl 25.0 parts l0 Cornstarch 1750 do.

200.0 parts Preparation:

The ingredients are intimately admixed with each other, and 200 mgm portions of the mixture are filled into gelatin capsules of suitable size. Each capsule contains mgm of the hexamethylenediamine compound and is an oral dosage unit composition with effective B-adrenergie receptor blocking and hypotensive ac- EXAMPLE 70 Hypodermic solution The solution is compounded from the following ingredients:

N,N'bis-[ 2'-hydroxy-3'-( 3"-trifluoromethyl-phcnoxy)-1'-propyl|-1,6-hexamerthylenediamine 2 HCl Sodium salt of EDTA (ethylenediamine tetraacetic acid) Distilled water Preparation:

The active ingredient and the EDTA salt are dissolved in a sufficient amount of distilled water, and the solution is diluted with water to the indicated weight. The solution is filtered until free from suspended particles and filled into 1 cc-ampules under aspetic conditiorl s. Finally, the ampules are sterilized and sealed. Each ampule contains 15 mgm of the hexamethylenediarpine compound, and the contents thereof are an injectable dosage unit composition with effective B-adrenergic receptor blocking and hypotensive action.

EXAMPLE "71 Coated sustained-release tablets 1 .5 parts q.s.ad 100.0 do.

The tablet core composition is compounded from the following ingredients:

ethylenediamine dihydrochloride Carboxymethyl cellulose (CMC) 295.0 do. Stearic acid 20.0 do. Celluloseacetate phthalatc (CAP) 40.0 do.

380.0 parts Preparation Dosage unit compositions containing a compound of the present invention as an active ingredient may, in addition, also contain one or more other active ingredients with different pharmacological activities, such as coronary dilators, sympathomimetics and tranquilizers, as illustrated by the following examples.

EXAMPLE 72 Coated sustained-release tablets The tablet core composition is compounded from the following ingredients:

enediamine 2 NC] 25.0 parts ()xazepam 20.0 do. Carhoxymethyl cellulose ((M() 295.0 do. Stearic acid 20.0 do. (elluloseaeetatephthalate (CAP) 40.0 do.

400.0 parts Preparation:

The tablets are manufactured in a manner analogous to that described in Example 71. Each tablet contains 25 mgm of the hexamethylencdiamine compound and 20 mgm of oxazepam. and is an oral dosage unit composition with effective fi-adrenergic receptor blocking, hypotcnsive and tranquilizing action.

EXAM PLE 73 Tablets The tablet composition is compounded from the following ingredients:

N,N'-his-l 2'-hydroxy-3'( 4"-acctaminophenoxy l '-propyl ll ,h-hexamethylenediamine 2 HC] 35.0 parts 2,6-his-(dicthanolanlino) 4,l4-dipipcridino-pyrimido| 5,4-d l-pyrimidine 75.0 do. Lactose l(14.() do. (orn starch l94.0 do. (olloidal silicic acid l4.0 do. Polyvinylpyrrolidonc (1.0 do. Magnesium stearatc 2.0 do. Soluble starch 10.0 do.

500.0 parts Preparation:

The active ingredients are intimately admixed with the lactose. the corn starch, the colloidal silicic acid and the polyvinylpyrrolidone, and the mixture is granulated in the usual way, using an aqueous solution of the soluble starch as the moistcner. The granulate is admixed with the magnesium stearate, and the composition is compressed into 500 mgm-tablets in a conventional tablet making machine. Each tablet contains 35 mgm of the hexamethylenediamine compound and 75 mgm of the pyrimidopyrimidine compound, and is an oral dosage unit composition with effective ,B-adrenergic receptor blocking, hypotensive and coronary dilating action.

Analogous results are obtained when any one of the other compounds embraced by formula I or a non-toxic acid addition salt thereof was substituted for the particular alkylenediamine derivative in Examples 68 through 73. Likewise, the amount of active ingredient in these illustrative examples may be varied to achieve the dosage unit range set forth above, and the amounts and nature of the inert pharmaceutical carrier ingredients may be varied to meet particular requirements.

While the present invention has been illustrated with the aid of certain specific embodiments thereof, it will be readily apparent to others skilled in the art that the invention is not limited to these particular embodiments, and that various changes and modifications may be made without departing from the spirit of the invention or the scope of the appended claims.

We claim:

1. A compound of the formula R, is -(CH ,-CN, where x is 0,1,2 or 3,

R is hydrogen, halogen, alkyl of l to 5 carbon atoms,

alkoxy of l to 5 carbon atoms, alkenyl of 2 to 5 carbon atoms or alkenyloxy of 2 to 5 carbon atoms;

R;, is hydrogen, halogen, alkyl of l to 5 carbon atoms or alkoxy of l to 5 carbon atoms;

R and R together with each other and the carbon atoms to which they are attached, form a saturated or unsaturated carbocyclic ring of up to 6 carbon atoms;

R, is hydrogen, alkyl of l to 5 carbon atoms or aralkyl; and

n is an integer from l to 10, inclusive;

or a non-toxic, pharamcologically acceptable acid addition salt thereof.

2. A compound of claim 1, which is of the formula R is hydrogen, halogen, alkyl of l to 5 carbon atoms, alkoxy of l to 5 carbon atoms, alkenyl of 2 to 5 car bon atoms or alkenyloxy of 2 to 5 carbon atoms;

R;, is hydrogen, halogen, alkyl of lto 5 carbon atoms or alkoxy of l to 5 carbon atoms;

R and R together with each other and the carbon atoms to which they are attached, form a saturated or unsaturated carbocyclic ring of up to 6 carbon atoms;

R, is hydrogen, alkyl of l to 5 carbon atoms or aralkyl; and

n is an integer from l to 10, inclusivey or a non-toxic, pharmacologically acceptable acid addition salt thereof.

3. A compound of claim 2, which is racemic or opti- UNITED STATES PATENI OFFICE CERTIFICATE OF CORRECTION Patent No. Dated Inventor(s) -f s1lLv '-1iu -IJQ\ It is certified that error appears in the above-identified patent and that said Letters Eateni. are hereby corrected as shown below:

llolumn l, .i

Tiolurnn Lin. should Column 23, Line 1- [SEAL] Arrest:

RUTH C. MASON Arresting Officer -'ln" should read- Signed and Scaled this ninth D ay 0f September I 975 8 "propar'glg loxg" shoulf: read --propar,qr,,;;lo:-:5:---

read "co "perioxide" should read peroxide "por ngl" should read propyl 53 I-ICl read ethanol -vn -a C. MARSHALL DANN (ummixsioncr uflarenrs and Trademarks 

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1, which is of the formula 175/8 wherein R2 is hydrogen, halogen, alkyl of 1 to 5 carbon atoms, alkoxy of 1 to 5 carbon atoms, alkenyl of 2 to 5 carbon atoms or alkenyloxy of 2 to 5 carbon atoms; R3 is hydrogen, halogen, alkyl of 1to 5 carbon atoms or alkoxy of 1 to 5 carbon atoms; R2 and R3, together with each other and the carbon atoms to which they are attached, form a saturated or unsaturated carbocyclic ring of up to 6 carbon atoms; R4 is hydrogen, alkyl of 1 to 5 carbon atoms or aralkyl; and n is an integer from 1 to 10, inclusive; or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 3. A compound of claim 2, which is racemic or optically active N,N''-bis-(2''-hydroxy-3''-92''''-cyano-phenoxy)-1''1n-propyl)-1,6 -hexamethylenediamine or a non-toxic, pharmacologically acceptable acid addition salt thereof.
 4. N,N''-bis(2''-hydroxy-3''-(2''''-cyano-phenoxy)-1''-n-propyl)-1,6 -hexamethylenediamine. 